Monitoring a condition of a subject

ABSTRACT

Apparatus and methods are described including a mechanical sensor configured to detect a physiological signal of a subject. A control unit receives the signal over a time duration of at least two hours at a given period of a first baseline day, and determines a baseline physiological parameter of the subject in response thereto. The control unit receives the signal over a time duration of at least two hours at a given period of a second day, the period on the second day overlapping with the period over which the signal is detected on the first baseline day. The control unit determines a physiological parameter of the subject based upon the detected signal on the second day, and compares the parameter to the subject&#39;s baseline physiological parameter. The control unit generates an alert in response to the comparison. Other applications are also described.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation-in-part of pending U.S. patentapplication Ser. No. 11/782,750 to Halperin, filed Jul. 25, 2007 (USPatent Application Publication No. 2008/0269625), which:

is a continuation-in-part of pending U.S. patent application Ser. No.11/446,281 to Lange (US Patent Application Publication No.2006/0224076), which is a continuation of U.S. patent application Ser.No. 11/048,100 to Lange (which is patented as U.S. Pat. No. 7,077,810),filed Jan. 31, 2005, which claims the benefit of U.S. Provisional PatentApplication 60/541,779 to Lange (which is abandoned) filed Feb. 5, 2004;

is a continuation-in-part of U.S. patent application Ser. No. 11/197,786to Halperin (which is patented as U.S. Pat. No. 7,314,451), filed Aug.3, 2005, which claims the benefit of (a) U.S. Provisional PatentApplication 60/674,382 to Lange (which is expired) filed Apr. 25, 2005,and (b) U.S. Provisional Patent Application 60/692,105 (which isexpired) to Lange, filed Jun. 21, 2005.

The present application is a continuation-in-part of pending U.S. patentapplication Ser. No. 11/552,872 to Pinhas (US Patent ApplicationPublication No. 2007/0118054), filed Oct. 25, 2006, which claims thebenefit of (a) U.S. Provisional Patent Application 60/731,934 toHalperin (which is expired), filed Nov. 1, 2005, (b) U.S. ProvisionalPatent Application 60/784,799 to Halperin (which is expired) filed Mar.23, 2006, and (c) U.S. Provisional Patent Application 60/843,672 toHalperin (which is expired), filed Sep. 12, 2006.

All of the above-mentioned applications are incorporated herein byreference.

FIELD OF EMBODIMENTS OF THE INVENTION

Some applications of the present invention relate generally topredicting and monitoring physiological conditions. Specifically, someapplications relate to methods and apparatus for monitoring a subject bymonitoring the subject's respiration rate and/or the subject's heartrate.

BACKGROUND

Chronic diseases are often expressed by episodic worsening of clinicalsymptoms. Preventive treatment of chronic diseases reduces the overalldosage of required medication and associated side effects, and lowersmortality and morbidity. Generally, preventive treatment should beinitiated or intensified as soon as the earliest clinical symptoms aredetected, in order to prevent progression and worsening of the clinicalepisode and to stop and reverse the pathophysiological process.Therefore, the ability to accurately monitor pre-episodic indicatorsincreases the effectiveness of preventive treatment of chronic diseases.

Many chronic diseases cause systemic changes in vital signs, such asbreathing and heartbeat patterns, through a variety of physiologicalmechanisms. For example, common respiratory disorders, such as asthma,chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF),are direct modifiers of breathing and/or heartbeat patterns. Otherchronic diseases, such as diabetes, epilepsy, and certain heartconditions (e.g., congestive heart failure (CHF)), are also known tomodify cardiac and breathing activity. In the case of certain heartconditions, such modifications typically occur because ofpathophysiologies related to fluid retention and general cardiovascularinsufficiency. Other signs such as coughing and sleep restlessness arealso known to be of importance in some clinical situations.

Many chronic diseases induce systemic effects on vital signs. Forexample, some chronic diseases interfere with normal breathing andcardiac processes during wakefulness and sleep, causing abnormalbreathing and heartbeat patterns.

Breathing and heartbeat patterns may be modified via various direct andindirect physiological mechanisms, resulting in abnormal patternsrelated to the cause of modification. Some respiratory diseases, such asasthma, and some heart conditions, such as CHF, are direct breathingmodifiers. Other metabolic abnormalities, such as hypoglycemia and otherneurological pathologies affecting autonomic nervous system activity,are indirect breathing modifiers.

Asthma is a chronic disease with no known cure. Substantial alleviationof asthma symptoms is possible via preventive therapy, such as the useof bronchodilators and anti-inflammatory agents. Asthma management isaimed at improving the quality of life of asthma patients.

Monitoring of lung function is viewed as a major factor in determiningan appropriate treatment, as well as in patient follow-up. Preferredtherapies are often based on aerosol-type medications to minimizesystemic side-effects. The efficacy of aerosol type therapy is highlydependent on patient compliance, which is difficult to assess andmaintain, further contributing to the importance of lung-functionmonitoring.

Asthma episodes usually develop over a period of several days, althoughthey may sometimes seem to appear unexpectedly. The gradual onset of theasthmatic episode provides an opportunity to start countermeasures tostop and reverse the inflammatory process. Early treatment at thepre-episode stage may reduce the clinical episode manifestationconsiderably, and may even prevent the transition from the pre-clinicalstage to a clinical episode altogether.

Two techniques are generally used for asthma monitoring. The firsttechnique, spirometry, evaluates lung function using a spirometer, aninstrument that measures the volume of air inhaled and exhaled by thelungs. Airflow dynamics are measured during a forceful, coordinatedinhalation and exhalation effort by the patient into a mouthpiececonnected via a tube to the spirometer. A peak-flow meter is a simplerdevice that is similar to the spirometer, and is used in a similarmanner. The second technique evaluates lung function by measuringnitric-oxide concentration using a dedicated nitric-oxide monitor. Thepatient breathes into a mouthpiece connected via a tube to the monitor.

Efficient asthma management requires daily monitoring of respiratoryfunction, which is generally impractical, particularly in non-clinicalor home environments. Peak-flow meters and nitric-oxide monitors providea general indication of the status of lung function. However, thesemonitoring devices do not possess predictive value, and are used asduring-episode markers. In addition, peak-flow meters and nitric-oxidemonitors require active participation of the patient, which is difficultto obtain from many children and substantially impossible to obtain frominfants.

CHF is a condition in which the heart is weakened and unable tocirculate blood to meet the body's needs. The subsequent buildup offluids in the legs, kidneys, and lungs characterizes the condition ascongestive. The weakening may be associated with either the left, right,or both sides of the heart, with different etiologies and treatmentsassociated with each type. In most cases, it is the left side of theheart which fails, so that it is unable to efficiently pump blood to thesystemic circulation. The ensuing fluid congestion of the lungs resultsin changes in respiration, including alterations in rate and/or pattern,accompanied by increased difficulty in breathing and tachypnea.

Quantification of such abnormal breathing provides a basis for assessingCHF progression. For example, Cheyne-Stokes Respiration (CSR) is abreathing pattern characterized by rhythmic oscillation of tidal volumewith regularly recurring periods of alternating apnea and hyperpnea.While CSR may be observed in a number of different pathologies (e.g.,encephalitis, cerebral circulatory disturbances, and lesions of thebulbar center of respiration), it has also been recognized as anindependent risk factor for worsening heart failure and reduced survivalin patients with CHF. In CHF, CSR is associated with frequent awakeningthat fragments sleep, and with concomitant sympathetic activation, bothof which may worsen CHF. Other abnormal breathing patterns may involveperiodic breathing, prolonged expiration or inspiration, or gradualchanges in respiration rate usually leading to tachypnea.

SUMMARY OF EMBODIMENTS

For some applications of the present invention, a subject's respirationrate is monitored for a duration of time of greater than two hours. Aparameter of the subject's respiration rate over the time duration, suchas the median respiration rate, the mean respiration rate, the maximumrespiration rate, and/or a pattern of the respiration rate isdetermined. The parameter is compared to the same parameter asdetermined on a previous day during a time period that overlaps with(e.g., is substantially the same as, or partially overlaps with) thetime period based upon which the parameter of respiration was determinedon the present day. For example, the parameter is compared to the sameparameter as determined on a previous day for the same time duration andat the same period (e.g., the same time) of the day. For example, themean respiration rate over a time duration of three hours, between thetimes of 8 pm and 11 pm on the present day, may be compared with themean respiration rate over a time duration of three hours between thetimes of 8 pm and 11 pm on the previous day. In response thereto, thelikelihood of the subject subsequently undergoing an adverse clinicalevent is determined. Typically, it is determined that the subject islikely to undergo an adverse clinical event by determining that thedifference between the parameter of respiration (e.g., the meanrespiration rate) of the present day and of the previous day is greaterthan a threshold amount, e.g., by determining that the parameter ofrespiration of the present day and that of the previous day aresubstantially different. Typically, in response to determining that thesubject is likely to undergo an adverse clinical event, an alert isgenerated.

For some applications, the techniques described in the above paragraphwith respect to the subject's respiration rate are applied with respectto the subject's heart rate and/or with respect to the subject'srespiration rate and the subject's heart rate. For example, it may bedetermined that the subject is likely to undergo an adverse clinicalevent by determining that the difference between a parameter of thesubject's cardiac cycle (e.g., the mean heart rate over a time durationof greater than two hours at a given period of the day) of the presentday and of a previous day is greater than a threshold amount, e.g., bydetermining that the parameter of the cardiac cycle of the present dayand that of the previous day are substantially different. Or, it may bedetermined that the subject is likely to undergo an adverse clinicalevent by determining that the difference between a parameter of thesubject's cardiac cycle of the present day and of a previous day isgreater than a threshold amount, and the difference between a parameterof the subject's respiration of the present day and of a previous day isgreater than a threshold amount.

For some applications of the present invention, a subject's motion ismonitored for a duration of time of greater than two hours. A parameterof the subject's motion, such as total duration that the subject is inmotion, or percentage of time that the subject is in motion, over thetime duration is determined. The parameter is compared to the sameparameter as determined on a previous day during a time period thatoverlaps with (e.g., is substantially the same as, or partially overlapswith) the time period based upon which the parameter of respiration wasdetermined on the present day. For example, the parameter is compared tothe same parameter as determined on a previous day for the same timeduration and at the same period (e.g., the same time) of the day. Forexample, the total time that the subject is in motion, or percentage oftime that the subject is in motion over a time duration of three hours,between the times of 8 pm and 11 pm on the present day, may be comparedwith the total time that the subject is in motion, or percentage of timethat the subject is in motion over a time duration of three hoursbetween the times of 8 pm and 11 pm on the previous day. In responsethereto, the likelihood of the subject subsequently undergoing anadverse clinical event is determined. Typically, it is determined thatthe subject is likely to undergo an adverse clinical event bydetermining that the difference between the parameter of motion of thepresent day and of the previous day is greater than a threshold amount,e.g., by determining that the parameter of motion of the present day andthat of the previous day are substantially different. Typically, inresponse to determining that the subject is likely to undergo an adverseclinical event, an alert is generated.

For some applications, the threshold of the cardiac cycle (describedhereinabove) is set responsively to a detected respiration rate, and/orresponsively to a detected parameter of the subject's motion.Alternatively or additionally, the threshold of the parameter of thesubject's respiration (described hereinabove) is set responsively to thedetected heart rate, and/or responsively to a detected parameter of thesubject's motion. Further alternatively or additionally, the thresholdof the parameter of the subject's motion (described hereinabove) is setresponsively to the detected heart rate, and/or responsively to thedetected respiration rate.

There is therefor provided, in accordance with some applications of thepresent invention, apparatus, including:

a mechanical sensor configured to detect a physiological signal of asubject without contacting or viewing the subject or clothes that thesubject is wearing;

a control unit configured to:

-   -   receive the physiological signal from the sensor over a time        duration of at least two hours at a given period of at least one        first baseline day,    -   determine a physiological parameter of the subject based upon        the received physiological signal of the first baseline day;    -   receive the physiological signal from the sensor over a time        duration of at least two hours at a given period of a second        day, the period over which the subject's physiological signal is        detected on the second day overlapping with the period over        which the subject's physiological signal is detected on the        first baseline day;    -   determine a physiological parameter of the subject based upon        the received physiological signal of the second day;    -   compare the physiological parameter based upon the received        physiological signal of the second day to the baseline        physiological parameter of the subject; and    -   generate an alert in response to the comparison; and

an output unit configured to output the alert.

For some applications, the physiological sensor is configured to detectthe physiological signal of the subject by detecting a respiration rateof the subject.

For some applications, the physiological sensor is configured to detectthe physiological signal of the subject by detecting a heart rate of thesubject.

For some applications, the physiological sensor is configured to detectthe physiological signal of the subject by detecting a parameter ofmotion of the subject.

There is further provided, in accordance with some applications of thepresent invention, apparatus, including:

a sensor configured to detect a respiration signal indicative of arespiration rate of a subject; and

a control unit configured to:

-   -   receive the detected respiration signal from the sensor over a        time duration of at least two hours at a given period of at        least one first respiration-rate baseline day;    -   determine a baseline parameter of the subject's respiration        based upon the received respiration signal of the first        respiration-rate baseline day;    -   receive the detected respiration signal from the sensor over a        time duration of at least two hours at a given period of a        second day, the period over which the subject's respiration is        detected on the second day overlapping with the period over        which the subject's respiration is detected on the first        respiration-rate baseline day;    -   determine a parameter of the subject's respiration based upon        the received respiration signal of the second day;    -   compare the parameter of the subject's respiration based upon        the received respiration signal of the second day to the        baseline parameter of the subject's respiration; and    -   generate an alert in response to the comparison; and    -   an output unit configured to output the alert.

For some applications, the control unit is configured to determine thebaseline parameter of respiration by determining a baseline respirationpattern based upon the received respiration signal of the firstrespiration-rate baseline day, and the control unit is configured todetermine the parameter of the subject's respiration based upon thereceived respiration signal of the second day by determining arespiration pattern based upon the received respiration signal of thesecond day.

For some applications:

the control unit is configured to determine the baseline parameter ofrespiration by determining a parameter selected from the groupconsisting of: a mean respiration rate, a maximum respiration rate, anda median respiration rate, based upon the received respiration signal ofthe first respiration-rate baseline day, and

the control unit is configured to determine the parameter of thesubject's respiration based upon the received respiration signal of thesecond day by determining a parameter selected from the group consistingof: a mean respiration rate, a maximum respiration rate, and a medianrespiration rate, based upon the received respiration signal of thesecond day.

For some applications, the control unit is configured to:

receive a heart-rate signal from the sensor indicative of a heart rateof the subject over a time duration of at least two hours at a givenperiod of at least one first heart-rate baseline day;

determine a baseline parameter of the subject's cardiac cycle based uponthe received heart-rate signal of the first heart-rate baseline day;

receive a heart-rate signal from the sensor indicative of a heart rateof the subject over a time duration of at least two hours at the givenperiod of the second day, the period over which the subject's heart rateis detected on the second day overlapping with the period over which thesubject's heart rate is detected on the first heart-rate baseline day;

determine a parameter of the subject's cardiac cycle based upon thereceived heart-rate signal of the second day; and

compare the parameter of the subject's cardiac cycle based upon thereceived heart-rate signal of the second day to the baseline parameterof the cardiac cycle, and

generate the alert by generating the alert in response to (a) thecomparison of the parameter of the subject's respiration based upon thereceived respiration signal of the second day to the baseline parameterof the subject's respiration, and (b) the comparison of the parameter ofthe subject's cardiac cycle based upon the received heart-rate signal ofthe second day to the baseline parameter of the subject's cardiac cycle.

For some applications, the control unit is configured to:

receive a motion signal from the sensor indicative of motion of thesubject over a time duration of at least two hours at a given period ofat least one first motion-parameter baseline day;

determine a baseline parameter of the subject's motion based upon thereceived motion signal of the first motion-parameter baseline day;

receive a motion signal from the sensor indicative of motion of thesubject over a time duration of at least two hours at the given periodof the second day, the period over which the subject's motion isdetected on the second day overlapping with the period over which thesubject's motion is detected on the first motion-parameter baseline day;

determine a parameter of the subject's motion based upon the receivedmotion signal of the second day; and

compare the parameter of the subject's motion based upon the receivedmotion signal of the second day to the baseline parameter of motion, and

generate the alert by generating the alert in response to (a) thecomparison of the parameter of the subject's respiration based upon thereceived respiration signal of the second day to the baseline parameterof the subject's respiration, and (b) the comparison of the parameter ofthe subject's motion based upon the received motion signal of the secondday to the baseline parameter of the subject's motion.

For some applications, the control unit is configured to compare theparameter of the subject's respiration based upon the receivedrespiration signal of the second day to the baseline parameter of thesubject's respiration by determining whether the parameter of thesubject's respiration based upon the received respiration signal of thesecond day differs from the baseline parameter of the subject'srespiration by more than a threshold amount.

For some applications, the control unit is configured to:

receive a heart-rate signal from the sensor indicative of a heart rateof the subject; and

set the threshold in response to the detected heart-rate signal.

For some applications, the control unit is configured to:

receive a motion signal from the sensor indicative of a motion of thesubject; and

set the threshold in response to the detected motion signal.

There is additionally provided, in accordance with some applications ofthe present invention, apparatus, including:

a sensor configured to detect a heart-rate signal indicative of a heartrate of a subject; and

a control unit configured to:

-   -   receive the detected heart-rate signal from the sensor over a        time duration of at least two hours at a given period of at        least one first heart-rate baseline day;    -   determine a baseline parameter of the subject's cardiac cycle        based upon the received heart-rate signal of the first        heart-rate baseline day;    -   receive the detected heart-rate signal from the sensor over a        time duration of at least two hours at a given period of a        second day, the period over which the subject's heart rate is        detected on the second day overlapping with the period over        which the subject's heart rate is detected on the first        heart-rate baseline day;    -   determine a parameter of the subject's cardiac cycle based upon        the received heart-rate signal of the second day;    -   compare the parameter of the subject's cardiac cycle based upon        the received heart-rate signal of the second day to the baseline        parameter of the subject's cardiac cycle; and    -   generate an alert in response to the comparison; and

an output unit configured to output the alert.

For some applications, the control unit is configured to:

receive a motion signal from the sensor indicative of motion of thesubject over a time duration of at least two hours at a given period ofat least one first motion-parameter baseline day;

determine a baseline parameter of the subject's motion based upon thereceived motion signal of the first motion-parameter baseline day;

receive a motion signal from the sensor indicative of motion of thesubject over a time duration of at least two hours at the given periodof the second day, the period over which the subject's motion isdetected on the second day overlapping with the period over which thesubject's motion is detected on the first motion-parameter baseline day;

determine a parameter of the subject's motion based upon the receivedmotion signal of the second day; and

compare the parameter of the subject's motion based upon the receivedmotion signal of the second day to the baseline parameter of motion, and

generate the alert by generating the alert in response to (a) thecomparison of the parameter of the subject's cardiac cycle based uponthe received heart-rate signal of the second day to the baselineparameter of the subject's cardiac cycle, and (b) the comparison of theparameter of the subject's motion based upon the received motion signalof the second day to the baseline parameter of the subject's motion.

For some applications, the control unit is configured to compare theparameter of the subject's cardiac cycle based upon the receivedheart-rate signal of the second day to the baseline parameter of thesubject's cardiac cycle by determining whether the parameter of thesubject's cardiac cycle based upon the received heart-rate signal of thesecond day differs from the baseline parameter of the subject's cardiaccycle by more than a threshold amount.

For some applications, the control unit is configured to:

receive a respiration signal from the sensor indicative of a respirationrate of the subject; and

set the threshold in response to the detected respiration signal.

For some applications, the control unit is configured to:

receive a motion signal from the sensor indicative of a motion of thesubject; and

set the threshold in response to the detected motion signal.

There is further provided, in accordance with some applications of thepresent invention, apparatus, including:

a sensor configured to detect a motion signal indicative of motion of asubject; and

a control unit configured to:

-   -   receive the detected motion signal from the sensor over a time        duration of at least two hours at a given period of at least one        first motion-parameter baseline day;    -   determine a baseline parameter of the subject's motion based        upon the received motion signal of the first motion-parameter        baseline day;    -   receive the detected motion signal from the sensor over a time        duration of at least two hours at a given period of a second        day, the period over which the subject's motion is detected on        the second day overlapping with the period over which the        subject's motion is detected on the first motion-parameter        baseline day;    -   determine a parameter of the subject's motion based upon the        received motion signal of the second day;    -   compare the parameter of the subject's motion based upon the        received motion signal of the second day to the baseline        parameter of the subject's motion; and    -   generate an alert in response to the comparison; and    -   an output unit configured to output the alert.

For some applications, the control unit is configured to compare theparameter of the subject's motion based upon the received motion signalof the second day to the baseline parameter of the subject's motion bydetermining whether the parameter of the subject's motion based upon thereceived motion signal of the second day differs from the baselineparameter of the subject's motion by more than a threshold amount.

For some applications, the control unit is configured to:

receive a respiration signal from the sensor indicative of a respirationrate of the subject; and

set the threshold in response to the detected respiration signal.

For some applications, the control unit is configured to:

receive a heart-rate signal from the sensor indicative of a heart rateof the subject; and

set the threshold in response to the detected heart-rate signal.

There is additionally provided, in accordance with some applications ofthe present invention, a method including:

detecting a respiration rate of a subject over a time duration of atleast two hours at a given period of at least one first respiration-ratebaseline day;

determining a baseline parameter of the subject's respiration based uponthe detected respiration rate for the first respiration-rate baselineday;

detecting a respiration rate of the subject over a time duration of atleast two hours at a given period of a second day, the period over whichthe subject's respiration is detected on the second day overlapping withthe period over which the subject's respiration is detected on the firstrespiration-rate baseline day;

determining a parameter of the subject's respiration based upon thedetected respiration rate on the second day;

comparing the parameter of the subject's respiration based upon thedetected respiration rate on the second day to the baseline parameter ofthe subject's respiration; and

generating an alert in response to the comparison.

There is further provided, in accordance with some applications of thepresent invention, a method including:

detecting a heart rate of a subject over a time duration of at least twohours at a given period of at least one first heart-rate baseline day;

determining a baseline parameter of the subject's cardiac cycle basedupon the detected heart rate for the first heart-rate baseline day;

detecting a heart rate of the subject over a time duration of at leasttwo hours at a given period of a second day, the period over which thesubject's heart rate is detected on the second day overlapping with theperiod over which the subject's heart rate is detected on the firstheart-rate baseline day;

determining a parameter of the subject's cardiac cycle based upon thedetected heart rate on the second day;

comparing the parameter of the subject's cardiac cycle based upon thedetected heart rate on the second day to the baseline parameter of thesubject's cardiac cycle; and

generating an alert in response to the comparison.

There is additionally provided, in accordance with some applications ofthe present invention, a method including:

detecting motion of a subject over a time duration of at least two hoursat a given period of at least one first motion-parameter baseline day;

determining a motion parameter of the subject's respiration based uponthe detected motion for the first motion-parameter baseline day;

detecting motion of the subject over a time duration of at least twohours at a given period of a second day, the period over which thesubject's motion is detected on the second day overlapping with theperiod over which the subject's motion is detected on the firstmotion-parameter baseline day;

determining a parameter of the subject's motion based upon the motiondetected on the second day;

comparing the parameter of the subject's motion based upon the motiondetected on the second day to the baseline parameter of the subject'smotion; and

generating an alert in response to the comparison.

There is further provided, in accordance with some applications of thepresent invention, a method including:

detecting a physiological signal of a subject over a time duration of atleast two hours at a given period of at least one first baseline day,without contacting or viewing the subject or clothes that the subject iswearing;

determining a physiological parameter of the subject based upon thedetected physiological signal for the first baseline day;

detecting the physiological signal of the subject over a time durationof at least two hours at a given period of a second day, the period overwhich the subject's physiological signal is detected on the second dayoverlapping with the period over which the physiological signal isdetected on the first baseline day;

determining a physiological parameter of the subject based upon thedetected physiological signal on the second day;

comparing the physiological parameter based upon the detectedphysiological signal on the second day to the baseline physiologicalparameter of the subject; and

generating an alert in response to the comparison.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a system for monitoring a chronicmedical condition of a subject, in accordance with some applications ofthe present invention;

FIG. 2 is a schematic block diagram illustrating components of a controlunit of the system of FIG. 1, in accordance with some applications ofthe present invention;

FIGS. 3A-D are graphs showing the results of experiments conducted, inaccordance with some applications of the present invention;

FIG. 4 is a graph illustrating breathing rate patterns of a chronicasthma patient, which is the same as FIG. 4 of U.S. Pat. No. 7,077,810to Lange, which is incorporated herein by reference;

FIGS. 5 and 6 are graphs of exemplary baseline and measured breathingrate and heart rate nighttime patterns, respectively, which aregenerally similar to FIGS. 6 and 7 of U.S. Pat. No. 7,314,451 toHalperin, which is incorporated herein by reference; and

FIG. 7 is a graph of baseline and breathing rate nighttime patterns,respectively, which is the same as FIG. 23 of U.S. Pat. No. 7,314,451 toHalperin.

DETAILED DESCRIPTION OF EMBODIMENTS

Reference is made to FIG. 1, which is a schematic illustration of asystem 10 for monitoring a chronic medical condition of a subject 12, inaccordance with some applications of the present invention. System 10typically comprises a mechanical sensor 30 (e.g., a motion sensor), acontrol unit 14, and a user interface 24. For some applications, userinterface 24 is integrated into control unit 14, as shown in the figure,while for other applications, the user interface and control unit areseparate units. For some applications, motion sensor is integrated intocontrol unit 14, in which case user interface 24 is either alsointegrated into control unit 14 or remote from control unit 14.

FIG. 2 is a schematic block diagram illustrating components of controlunit 14, in accordance with some applications of the present invention.Control unit 14 typically comprises a motion data acquisition module 20and a pattern analysis module 16. Pattern analysis module 16 typicallycomprises one or more of the following modules: a breathing patternanalysis module 22, a heartbeat pattern analysis module 23, a coughanalysis module 26, a restlessness analysis module 28, a blood pressureanalysis module 29, and an arousal analysis module 31. For someapplications, two or more of analysis modules 20, 22, 23, 26, 28, 29,and 31 are packaged in a single housing. For other applications, themodules are packaged separately (for example, so as to enable remoteanalysis by one or more of the pattern analysis modules of breathingsignals acquired locally by data acquisition module 20). For someapplications, user interface comprises a dedicated display unit such asan LCD or CRT monitor. Alternatively or additionally, user interface 24includes a communication line for relaying the raw and/or processed datato a remote site for further analysis and/or interpretation.

For some applications of the present invention, data acquisition module20 is adapted to non-invasively monitor breathing and heartbeat patternsof subject 12. Breathing pattern analysis module 22 and heartbeatpattern analysis module are adapted to analyze the respective patternsin order to (a) predict an approaching clinical event, such as an asthmaattack or heart condition-related lung fluid buildup, and/or (b) monitorthe severity and progression of a clinical event as it occurs. For someapplications, breathing pattern analysis module 22 and heartbeat patternanalysis module 23 are adapted to analyze the respective patterns inorder to determine a likelihood of an approaching adverse clinical eventwithout necessarily identifying the nature of the event. User interface24 is adapted to notify subject 12 and/or a healthcare worker of thepredicted or occurring event. Prediction of an approaching clinicalevent facilitates early preventive treatment, which generally reducesthe required dosage of medication, and/or lowers mortality andmorbidity. When treating asthma, such a reduced dosage generallyminimizes the side-effects associated with high dosages typicallyrequired to reverse the inflammatory condition once the event has begun.

For some applications of the present invention, pattern analysis module16 combines parameter data generated from two or more of analysismodules 20, 22, 23, 26, 28, 29, and analyzes the combined data in orderto predict and/or monitor a clinical event. For some applications,pattern analysis module 16 derives a score for each parameter based onthe parameter's deviation from baseline values (either for the specificpatient or based on population averages). Pattern analysis module 16combines the scores, such as by taking an average, maximum, standarddeviation, or other function of the scores. The combined score iscompared to one or more threshold values (which may be predetermined) todetermine whether an event is predicted, currently occurring, or neitherpredicted nor occurring, and/or to monitor the severity and progressionof an occurring event. For some applications, pattern analysis module 16learns the criteria and/or functions for combining the individualparameter scores for the specific patient or patient group based onpersonal history. For example, pattern analysis module 16 may performsuch learning by analyzing parameters measured prior to previousclinical events.

Although system 10 may monitor breathing and heartbeat patterns at anytime, for some conditions it is generally most effective to monitor suchpatterns during sleep at night. When the subject is awake, physical andmental activities unrelated to the monitored condition often affectbreathing and heartbeat patterns. Such unrelated activities generallyhave less influence during most night sleep. For some applications,system 10 monitors and records patterns throughout all or a largeportion of a night. The resulting data set generally encompasses typicallong-term respiratory and heartbeat patterns, and facilitatescomprehensive analysis. Additionally, such a large data set enablesrejection of segments contaminated with movement or other artifacts,while retaining sufficient data for a statistically significantanalysis.

Reference is again made to FIG. 2. Data acquisition module 20 typicallycomprises circuitry for processing the raw motion signal generated bymotion sensor 30, such as at least one pre-amplifier 32, at least onefilter 34, and an analog-to-digital (A/D) converter 36. Filter 34typically comprises a band-pass filter or a low-pass filter, serving asan anti-aliasing filter with a cut-off frequency of less than one halfof the sampling rate. The low-passed data is typically digitized at asampling rate of at least 10 Hz and stored in memory. For example, theanti-aliasing filter cut-off may be set to 5 Hz and the sampling rateset to 40 Hz.

Reference is again made to FIG. 1. Typically, motion sensor 30 detectsone or more physiological signal of the subject without contacting orviewing the subject or clothes that the subject is wearing. For someapplications of the present invention, motion sensor 30 comprises apressure gauge (e.g., a piezoelectric sensor) or a strain gauge (e.g., asilicon or other semiconductor strain gauge, or a metallic straingauge), which is typically adapted to be installed in, on, or under areclining surface 37 upon which the subject lies, e.g., sleeps, and tosense breathing- and heartbeat-related motion of the subject. “Pressuregauge,” as used in the claims, includes, but is not limited to, all ofthe gauges mentioned in the previous sentence. Typically, recliningsurface 37 comprises a mattress, a mattress covering, a sheet, amattress pad, and/or a mattress cover. For some applications, motionsensor 30 is integrated into reclining surface 37, e.g., into amattress, and the motion sensor and reclining surface are providedtogether as an integrated unit. For some applications, motion sensor 30is adapted to be installed in, on, or under reclining surface 37 in avicinity of an abdomen 38 or chest 39 of subject 12. Alternatively oradditionally, motion sensor 30 is installed in, on, or under recliningsurface 37 in a vicinity of a portion of subject 12 anatomically below awaist of the subject, such as in a vicinity of legs 40 of the subject.For some applications, such positioning provides a clearer pulse signalthan positioning the sensor in a vicinity of abdomen 38 or chest 39 ofthe subject. For some applications, motion sensor 30 comprises a fiberoptic sensor, for example, as described by Butter and Hocker in AppliedOptics 17: 2867-2869 (Sep. 15, 1978).

For some applications, the pressure or strain gauge is encapsulated in arigid compartment, which typically has a surface area of at least 10cm^2, and a thickness of less than 5 mm. The gauge output is channeledto an electronic amplifier, such as a charge amplifier typically usedwith piezoelectric accelerometers and capacitive transducers tocondition the extremely high output impedance of the transducer to a lowimpedance voltage suitable for transmission over long cables. The straingauge and electronic amplifier translate the mechanical vibrations intoelectrical signals. Alternatively, the strain gauge output is amplifiedusing a Wheatstone bridge and an amplifier such as Analog Device ModuleNumbers 3B16, for a minimal bandwidth, or 3B18, for a wider bandwidth(National Instruments Corporation, Austin, Tex., USA).

For some applications of the present invention, motion sensor 30comprises a grid of multiple pressure or strain gauge sensors, adaptedto be installed in, on, or under reclining surface 37. The use of such agrid, rather than a single gauge, may improve breathing and heartbeatsignal reception.

Breathing pattern analysis module 22 is adapted to extract breathingpatterns from the motion data, and heartbeat pattern analysis module 23is adapted to extract heartbeat patterns from the motion data.Alternatively or additionally, system 10 comprises another type ofsensor, such as an acoustic or air-flow sensor, attached or directed atthe subject's face, neck, chest and/or back.

For some applications of the present invention, the subject'srespiration rate is monitored for a duration of time of greater than twohours (e.g., greater than three hours, greater than four hours, greaterthan five hours, or greater than six hours). Breathing pattern analysismodule 22 determines a parameter of the subject's respiration rate overthe time duration, such as the median respiration rate, the meanrespiration rate, the maximum respiration rate, and/or a respirationrate pattern. Module 22 compares the determined parameter to the sameparameter as determined on a previous day during a time period thatoverlaps with the time period based upon which the parameter ofrespiration was determined on the present day. For example, theparameter is compared to the same parameter as determined on a previousday for the same time duration and at the same period (e.g., the sametime) of the day.

For example, the mean respiration rate over a time duration of threehours, between the times of 8 pm and 11 pm on the present day, may becompared with the mean respiration rate over a time duration of threehours between the times of 8 pm and 11 pm on the previous day. Inresponse thereto, the likelihood of the subject subsequently undergoingan adverse clinical event is determined. Typically, it is determinedthat the subject is likely to undergo an adverse clinical event bydetermining that the difference between the parameter of respiration(e.g., the mean respiration rate) of the present day and of the previousday is greater than a threshold amount. Typically, in response todetermining that the subject is likely to undergo an adverse clinicalevent, an alert is generated by user interface 24.

For some applications, the period of to the day which is compared to thesame period of the previous day is a time period, e.g., between 8 pm and11 pm, as described hereinabove. Alternatively, the period may bedefined with respect to the subject's circadian clock, e.g., the periodmay be the first three hours of the subject's sleep, or from thebeginning of the second hour of the subject's sleep to the end of thefifth hour of the subject's sleep.

For some applications, heartbeat pattern analysis module 23 appliesgenerally similar analysis to the subject's heart rate to that describedhereinabove with respect to the breathing pattern analysis module 22.For example, module 23 may determine that the subject is likely toundergo an adverse clinical event by determining that the differencebetween a parameter of the subject's cardiac cycle (e.g., the mean heartrate over a time duration of greater than two hours at a given period ofthe day) on the present day and that of a previous day is greater than athreshold amount. For some applications, control unit 24 determines thatthe subject is likely to undergo an adverse clinical event bydetermining that the difference between a parameter of the subject'scardiac cycle on the present day and that of a previous day is greaterthan a threshold amount, and the difference between a parameter of thesubject's respiration on the present day and that of the previous day isgreater than a threshold amount.

As described hereinabove, for some applications, breathing patternanalysis module 22 and heartbeat pattern analysis module are adapted toanalyze the respective patterns in order to determine a likelihood of anapproaching adverse clinical event without necessarily identifying thenature of the event. Thus, for some applications, in response todetermining that the subject is likely to undergo an adverse clinicalevent, the user interface generates a generic alert signal, in order toindicate to a healthcare professional that an adverse clinical event isimminent.

For some applications, system 10 applies generally similar analysis to adifferent physiological parameter of the subject to that describedhereinabove with respect to the breathing pattern analysis module 22.For example, the system may apply the analysis to a parameter of thesubject's motion, such as the total time that the subject is in motion,or percentage of time that the subject is in motion over a given timeduration.

Reference is now made to FIGS. 3A-D, which are graphs showing theresults of experiments conducted, in accordance with some applicationsof the present invention. Earlysense Ltd. (Israel) manufactures theEverOn™ system, which is a contact-less piezoelectric sensor placedunder a subject's mattress that provides continuous measurement of heartrate and respiration rate of the subject, generally in accordance withthe techniques described hereinabove.

A non-interventional study was conducted in two internal medicinedepartments (Sheba Medical Center and Meir Medical Center, both inIsrael). Patients who were admitted due to an acute respiratorycondition were enrolled on the study. Patients were monitored by theEverOn™ sensor and followed for major clinical episodes. A majorclinical event was defined as death, transfer to ICU, or intubation andmechanical ventilation on the floors. Out of 149 patients included inthe study, 96 patients had a length of stay that allowed at least onecomparable time window. Ten major clinical events were recorded forthese patients. Retrospective analysis of continuous respiratory andheart signal recording was performed. The median respiration rate andheart rate over 6-hour time durations (00-06, 06-12, 12-18, and 18-24)were compared to the median respiration rate and heart rate over acorresponding 6-hour time duration on the previous day. Similarly, themaximum respiration rate and heart rate over 6-hour time durations(00-06, 06-12, 12-18, and 18-24) were compared to the maximumrespiration rate and heart rate over a corresponding 6-hour timeduration on the previous day. Retrospective receiver operatingcharacteristic (ROC) curve analysis was applied to the results todetermine the sensitivity, specificity, positive predictive value, andnegative predictive value of using respective thresholds (i.e.,thresholds for the difference between median or maximum respiration rateor heart rate and those of the previous day) for determining thelikelihood of a subject undergoing (a) any adverse clinical event, i.e.,either a major or a moderate clinical event (such as a non-majorrespiratory event requiring immediate intervention, e.g., bilevelpositive airway pressure (BIPAP) or continuous positive airway pressure(CPAP)), or (b) a major clinical event.

Table 1 (shown below) shows the results of the ROC curve analysis ofrespective combinations of median heart rate and respiration ratethresholds (i.e., thresholds for the difference between median heartrate and respiration rate and those of the previous day) with respect todetermining the likelihood of a subject undergoing any adverse clinicalevent, i.e., either a major or a moderate clinical event.

TABLE 1 Threshold Heart rate (beats per minute) − Respiration rate(breaths per minute)) Sensitivity Specificity PPV NPV 14 − 3 67 82 35 9514 − 4 67 82 35 95 14 − 5 67 86 40 95 14 − 6 58 89 44 94 16 − 3 67 87 4295 16 − 4 67 87 42 95 16 − 5 67 89 47 95 16 − 6 58 93 54 94 18 − 3 67 8947 95 18 − 4 67 89 47 95 18 − 5 67 90 50 95 18 − 6 58 94 58 94 20 − 3 6794 62 95 20 − 4 67 94 62 95 20 − 5 67 95 67 95 20 − 6 58 98 78 94 22 − 367 94 62 95 22 − 4 67 94 62 95 22 − 5 67 95 67 95 22 − 6 58 98 78 94

Table 2 (shown below) shows the results of the ROC curve analysis ofrespective combinations of median heart rate and respiration rate (i.e.,thresholds for the difference between median heart rate and respirationrate and those of the previous day) thresholds with respect todetermining the likelihood of a subject undergoing a major clinicalevent.

TABLE 2 Threshold (Heart rate (beats per minute) − Respiration rate(breaths per minute)) Sensitivity Specificity PPV NPV   −3 80 83 35 9714 − 4 80 83 35 97 14 − 5 80 86 40 97 14 − 6 70 90 44 96 16 − 3 80 87 4297 16 − 4 80 87 42 97 16 − 5 80 90 47 97 16 − 6 70 93 54 96 18 − 3 80 9047 97 18 − 4 80 90 47 97 18 − 5 80 91 50 98 18 − 6 70 94 58 96 20 − 3 8094 62 98 20 − 4 80 94 62 98 20 − 5 80 95 67 98 20 − 6 70 98 78 97 22 − 380 94 62 98 22 − 4 80 94 62 98 22 − 5 80 95 67 98 22 − 6 70 98 78 97

It is noted with respect to Tables 1 and 2 that the greatest sum ofsensitivity and specificity is for thresholds of 20 or 22 for medianheart rate in combination with a threshold of 5 for median respirationrate, both for predicting all adverse clinical events (i.e., major andminor adverse clinical events), and for predicting major clinicalevents.

Thus, for some applications of the present invention, a subject's heartrate and respiration rate are monitored. The median (or mean, ormaximum) heart rate and respiration rate over a time duration of morethan two hours and less than eight hours (e.g., greater than threehours, greater than four hours, greater than five hours, or greater thansix hours) is determined and is compared to the median (or mean, ormaximum) heart rate and respiration rate over a similar time duration ata similar period of the day (e.g., at the same time of day) on at leastone previous day (e.g., the previous day). In response to determining(a) that the median (or mean, or maximum) heart rate on the present daydiffers from that of the previous day by a threshold amount of more than15 beats per minute, e.g., more than 18 beats per minute, and (b) thatthe median (or mean, or maximum) respiration rate of the present daydiffers from that of the previous day by a threshold amount of more than3 breaths per minute, e.g., more than 4 breaths per minute, then analert is generated in order to indicate that an adverse clinical eventis likely to occur.

Table 3 (shown below) shows the results of the ROC curve analysis ofrespective maximum heart rate thresholds (i.e., thresholds for thedifference between the maximum heart rate and that of the previous day)with respect to determining the likelihood of a subject undergoing amajor or a moderate clinical event.

TABLE 3 Heart rate threshold Sum of (beats Sensitivity per and minute)Sensitivity Specificity Specificity 0.00 1.00 0.00 1.00 0.25 1.00 0.011.01 1.00 1.00 0.02 1.02 3.00 0.92 0.07 0.99 4.00 0.83 0.11 0.94 4.500.83 0.17 1.00 5.00 0.83 0.19 1.02 6.00 0.75 0.25 1.00 7.00 0.75 0.321.07 8.00 0.75 0.38 1.13 8.50 0.67 0.46 1.13 9.00 0.67 0.48 1.14 10.000.67 0.54 1.20 11.00 0.67 0.62 1.29 11.50 0.67 0.70 1.37 12.00 0.67 0.711.38 13.00 0.67 0.75 1.42 13.50 0.67 0.79 1.45 14.00 0.67 0.80 1.4615.00 0.67 0.82 1.49 16.00 0.67 0.85 1.51 17.00 0.67 0.86 1.52 18.000.67 0.87 1.54 19.00 0.67 0.89 1.56 20.00 0.67 0.90 1.57 21.00 0.67 0.921.58 22.00 0.67 0.93 1.60 22.75 0.58 0.93 1.51 25.00 0.58 0.94 1.5227.00 0.50 0.95 1.45 28.00 0.42 0.95 1.37 29.00 0.33 0.95 1.29 30.750.17 0.95 1.12 32.00 0.08 0.95 1.04 33.00 0.08 0.96 1.05 34.00 0.08 0.981.06 53.00 0.00 0.98 0.98 56.00 0.00 0.99 0.99

It is noted with respect to Table 3 that the greatest sum of sensitivityand specificity is for a heart rate threshold of 22 beats per minute,for predicting major and moderate adverse clinical events. FIG. 3A showsthe ROC curve for a heart rate threshold of 22 with respect topredicting a likelihood of either a major or a moderate adverse clinicalevent. The area under the curve is 0.70 with a standard deviation of0.11 and a p-value of 0.026.

Table 4 (shown below) shows the results of the ROC curve analysis ofrespective maximum heart rate thresholds (i.e., thresholds for thedifference between the maximum heart rate and that of the previous day)with respect to determining the likelihood of a subject undergoing amajor clinical event.

TABLE 4 Heart rate threshold Sum of (beats per Sensitivity and minute)Sensitivity Specificity Specificity 0.00 1.00 0.00 1.00 0.25 1.00 0.011.01 1.00 1.00 0.02 1.02 3.00 1.00 0.08 1.08 4.00 0.90 0.12 1.02 4.500.90 0.17 1.07 5.00 0.90 0.20 1.10 6.00 0.80 0.26 1.06 7.00 0.80 0.331.13 8.00 0.80 0.38 1.18 8.50 0.80 0.48 1.28 9.00 0.80 0.49 1.29 10.000.80 0.55 1.35 11.00 0.80 0.63 1.43 11.50 0.80 0.71 1.51 12.00 0.80 0.721.52 13.00 0.80 0.76 1.56 13.50 0.80 0.79 1.59 14.00 0.80 0.80 1.6015.00 0.80 0.83 1.63 16.00 0.80 0.85 1.65 17.00 0.80 0.86 1.66 18.000.80 0.87 1.67 19.00 0.80 0.90 1.70 20.00 0.80 0.91 1.71 21.00 0.80 0.921.72 22.00 0.80 0.93 1.73 22.75 0.70 0.93 1.63 25.00 0.70 0.94 1.6427.00 0.60 0.95 1.55 28.00 0.50 0.95 1.45 29.00 0.40 0.95 1.35 30.750.20 0.95 1.15 32.00 0.10 0.95 1.05 33.00 0.10 0.97 1.07 34.00 0.10 0.981.08 53.00 0.00 0.98 0.98 56.00 0.00 0.99 0.99

It is noted with respect to Table 4 that the greatest sum of sensitivityand specificity is for a heart rate threshold of beats per minute forpredicting major adverse clinical events. FIG. 3B shows the ROC curvefor a heart rate threshold of 22 with respect to predicting a likelihoodof a major adverse clinical event. The area under the curve is 0.79 witha standard deviation of 0.11 and a p-value of 0.0024.

In general, in accordance with the indications provided by the data inTables 3 and 4 and in FIGS. 3A and 3B, a subject's heart rate ismonitored. The median (or mean, or maximum) heart rate over a timeduration of more than two hours and less than eight hours (e.g., greaterthan three hours, greater than four hours, greater than five hours, orgreater than six hours) is determined and is compared to the median (ormean, or maximum) heart rate over a similar time duration at a similarperiod of the day (e.g., at the same time of day) on at least oneprevious day (e.g., the previous day). In response to determining (a)that the median (or mean, or maximum) heart rate of the present daydiffers from that of the previous day by a threshold amount of more than15 beats per minute (e.g., more than 18 beats per minute, e.g., morethan 20 beats per minute), and/or less than beats per minute, then analert is generated in order to indicate that an adverse clinical eventis likely to occur.

Table 5 (shown below) shows the results of the ROC curve analysis ofrespective maximum respiration rate thresholds (i.e., thresholds for thedifference between the maximum respiration rate and that of the previousday), with respect to determining the likelihood of a subject undergoinga major or a moderate clinical event.

TABLE 5 Respiration rate Sum of threshold Sensitivity (breaths per andminute) Sensitivity Specificity Specificity 0.00 1.00 0.00 1.00 0.501.00 0.05 1.05 1.00 1.00 0.06 1.06 1.50 1.00 0.24 1.24 2.00 1.00 0.261.26 3.00 1.00 0.43 1.43 3.50 1.00 0.58 1.58 4.00 1.00 0.59 1.59 5.001.00 0.70 1.70 6.00 0.69 0.76 1.46 6.50 0.54 0.83 1.37 6.75 0.54 0.851.39 7.00 0.46 0.85 1.31 7.50 0.38 0.89 1.28 8.00 0.31 0.89 1.20 9.000.23 0.92 1.15 10.00 0.23 0.92 1.16 12.00 0.23 0.93 1.16 16.00 0.23 0.971.20 18.00 0.15 0.97 1.13 19.00 0.08 0.98 1.06 24.00 0.00 0.98 0.9835.00 0.00 0.99 0.99

It is noted with respect to Table 5 that the greatest sum of sensitivityand specificity is for a respiration rate threshold of 5 breaths perminute, for predicting major and moderate adverse clinical events. FIG.3C shows the ROC curve for a respiration rate threshold of 5 withrespect to predicting a likelihood of either a major or a moderateadverse clinical event. The area under the curve is 0.84 with a standarddeviation of 0.04, and a p-value of 0.000049.

Table 6 (shown below) shows the results of the ROC curve analysis ofrespective respiration rate thresholds (i.e., thresholds for thedifference between the maximum respiration rate and that of the previousday), with respect to determining the likelihood of a subject undergoinga major clinical event.

TABLE 6 Respiration Sum of rate threshold Sensitivity (breaths per andminute) Sensitivity Specificity Specificity 0.00 1.00 0.00 1.00 0.501.00 0.05 1.05 1.00 1.00 0.06 1.06 1.50 1.00 0.23 1.23 2.00 1.00 0.261.26 3.00 1.00 0.42 1.42 3.50 1.00 0.57 1.57 4.00 1.00 0.58 1.58 5.001.00 0.69 1.69 6.00 0.73 0.76 1.49 6.50 0.55 0.83 1.37 6.75 0.55 0.841.39 7.00 0.55 0.85 1.40 7.50 0.45 0.89 1.35 8.00 0.36 0.89 1.26 9.000.27 0.92 1.19 10.00 0.27 0.93 1.20 12.00 0.27 0.93 1.21 16.00 0.27 0.971.24 18.00 0.18 0.98 1.16 19.00 0.09 0.98 1.07 24.00 0.00 0.98 0.9835.00 0.00 0.99 0.99

It is noted with respect to Table 6 that the greatest sum of sensitivityand specificity is for a respiration rate threshold of 5 breaths perminute for predicting major adverse clinical events. FIG. 3D shows theROC curve for a respiration rate threshold of 5 with respect topredicting a likelihood of a major adverse clinical event. The areaunder the curve is 0.85 with a standard deviation of 0.04, and a p-valueof 0.00012.

In general, in accordance with the indications provided by the data inTables 5 and 6 and in FIGS. 3C and 3D, a subject's respiration rate ismonitored. The median (or mean, or maximum) respiration rate over a timeduration of more than two hours and less than eight hours (e.g., greaterthan three hours, greater than four hours, greater than five hours, orgreater than six hours) is determined and is compared to the median (ormean, or maximum) respiration rate over a similar time duration at asimilar period of the day (e.g., at the same time of day) on at leastone previous day (e.g., the previous day). In response to determining(a) that the median (or mean, or maximum) respiration rate of thepresent day differs from that of the previous day by a threshold amountof more than 3 breaths per minute (e.g., more than 4 breaths perminute), and/or less than 10 breaths per minute (e.g., less than eight,or less than six breaths per minute), then an alert is generated inorder to indicate that an adverse clinical event is likely to occur.

For some applications, the techniques described herein are used incombination with the techniques described in one or more of thefollowing references, both of which are incorporated herein byreference:

-   U.S. Pat. No. 7,077,810 to Lange; and/or-   U.S. Pat. No. 7,314,451 to Halperin.

For example, for some applications, as is generally described in U.S.Pat. No. 7,077,810 to Lange, pattern analysis module 22 is configured topredict the onset of an asthma attack or a different clinical event,and/or monitor its severity and progression. Module 22 typicallyanalyzes changes in breathing rate and in breathing rate variabilitypatterns in combination to predict the onset of an asthma attack.Although breathing rate typically slightly increases prior to the onsetof an attack, this increase alone is not always a specific marker of theonset of an attack. Therefore, in order to more accurately predict theonset of an attack, and monitor the severity and progression of anattack, module 22 typically additionally analyzes changes in breathingrate variability patterns. For some applications, module 22 compares oneor more of the following patterns to respective baseline patterns, andinterprets a deviation from baseline as indicative of (a) the onset ofan attack, and/or (b) the severity of an attack in progress:

-   -   a slow trend breathing rate pattern. Module 22 interprets as        indicative of an approaching or progressing attack an increase        vs. baseline, for example, for generally healthy subjects, an        attenuation of the typical segmented, monotonic decline of        breathing rate typically over at least 1 hour, e.g., over at        least 2, 3, or 4 hours, or the transformation of this decline        into an increasing breathing rate pattern, depending on the        severity of the attack;    -   a breathing rate variability pattern. Module 22 interprets as        indicative of an approaching or progressing attack a decrease in        breathing rate variability. Such a decrease generally occurs as        the onset of an episode approaches, and intensifies with the        progression of shortness of breath during an attack;    -   a breathing duty-cycle pattern. Module 22 interprets a        substantial increase in the breathing duty-cycle as indicative        of an approaching or progressing attack. Breathing duty-cycle        patterns include, but are not limited to, inspirium time/total        breath cycle time, expirium time/total breath cycle time, and        (inspirium+expirium time)/total breath cycle time; and    -   interruptions in breathing pattern such as caused by coughs,        sleep disturbances, or waking. Module 22 quantifies these        events, and determines their relevance to prediction of        potential asthma attacks.

Reference is made to FIG. 4, which is a graph illustrating breathingrate patterns of a chronic asthma patient, and which is the same as FIG.4 of U.S. Pat. No. 7,077,810 to Lange. Breathing of the asthma patientwas monitored during sleep on several nights. The patient's breathingrate was averaged for each hour of sleep (excluding periods of rapid eyemovement (REM) sleep). During the first approximately two months thatthe patient was monitored, the patient did not experience any episodesof asthma. A line 100 is representative of a typical slow trendbreathing pattern recorded during this non-episodic period, and thusrepresents a baseline slow trend breathing rate pattern for thispatient. It should be noted that, unlike the monotonic decline inbreathing rate typically observed in non-asthmatic patients, thebaseline breathing rate pattern of the chronically asthmatic patient ofthe experiment reflects an initial decline in breathing rate during thefirst few hours of sleep, followed by a gradual increase in breathingrate throughout most of the rest of the night.

Lines 102 and 104 were recorded on two successive nights at theconclusion of the approximately two-month period, line 102 on the firstof these two nights, and line 104 on the second of these two nights. Thepatient experienced an episode of asthma during the second of thesenights. Lines 102 and 104 thus represent a pre-episodic slow trendbreathing rate pattern and an episodic slow trend breathing ratepattern, respectively. As can be seen in the graph, the patient'sbreathing rate was substantially elevated vs. baseline during all hoursof the pre-episodic night, and even further elevated vs. baseline duringthe episodic night.

Using techniques described herein, the pattern of line 102 is comparedwith the baseline pattern of line 100, in order to predict that thepatient may experience an asthmatic episode. The pattern of line 104 iscompared with the baseline pattern of line 100 in order to assess aprogression of the asthmatic episode.

In accordance with the data shown in FIG. 4, for some applications, asubject's respiration is detected on first and second days over similartime durations and at similar time periods (e.g., during the first two,three four, five, or six hours of the subject's sleep). A parameter ofthe subject's respiration based upon the detected respiration rate onthe second day is compared with that of the first day. An alert isgenerated in response to the comparison indicating that an adverseclinical event is approaching, e.g., in response to determining that thedifference between the median, the mean, and/or the maximum respirationrate on the second day and that of the first day exceeds a threshold.

For some applications, techniques as described in U.S. Pat. No.7,314,451 to Halperin are used in conjunction with the techniquesdescribed herein. For example, for some applications, system 10 monitorsand records patterns throughout all or a large portion of a night. Theresulting data set generally encompasses typical long-term respiratoryand heartbeat patterns, and facilitates comprehensive analysis.Additionally, such a large data set enables rejection of segmentscontaminated with movement or other artifacts, while retainingsufficient data for a statistically significant analysis.

Although breathing rate typically slightly increases prior to the onsetof an asthma attack (or a different adverse clinical event), thisincrease alone is not always a specific marker of the onset of anattack. Therefore, in order to more accurately predict the onset of anattack, and monitor the severity and progression of an attack, in anembodiment of the present invention, breathing pattern analysis module22 additionally analyzes changes in breathing rate variability patterns.For some applications, module 22 compares one or more of the followingpatterns to respective baseline patterns, and interprets a deviationfrom baseline as indicative of (a) the onset of an attack, and/or (b)the severity of an attack in progress:

-   -   a slow trend breathing rate pattern. Module 22 interprets as        indicative of an approaching or progressing attack an increase        vs. baseline, for example, for generally healthy subjects, an        attenuation of the typical segmented, monotonic decline of        breathing rate typically over at least 1 hour, e.g., over at        least 2, 3, or 4 hours, or the transformation of this decline        into an increasing breathing rate pattern, depending on the        severity of the attack;    -   a breathing rate pattern. Module 22 interprets as indicative of        an approaching or progressing attack an increase or lack of        decrease in breathing rate during the first several hours of        sleep, e.g., during the first 2, 3, or 4 hours of sleep.    -   a breathing rate variability pattern. Module 22 interprets a        decrease in breathing rate variability as indicative of an        approaching or progressing attack. Such a decrease generally        occurs as the onset of an episode approaches, and intensifies        with the progression of shortness of breath during an attack;    -   a breathing duty-cycle pattern. Module 22 interprets a        substantial increase in the breathing duty-cycle as indicative        of an approaching or progressing attack. Breathing duty-cycle        patterns include, but are not limited to, inspirium time/total        breath cycle time, expirium time/total breath cycle time, and        (inspirium+expirium time)/total breath cycle time;    -   a change in breathing rate pattern towards the end of night        sleep (typically between about 3:00 A.M. and about 6:00 A.M.);        and    -   interruptions in breathing pattern such as caused by coughs,        sleep disturbances, or waking. Module 22 quantifies these        events, and determines their relevance to prediction of        potential asthma attacks.

Pattern analysis modules 22 and 23 typically determine baseline patternsby analyzing breathing and/or heart rate patterns, respectively, of thesubject during non-symptomatic nights. Alternatively or additionally,modules 22 and 23 are programmed with baseline patterns based onpopulation averages. For some applications, such population averages aresegmented by characteristic traits such as age, height, weight, andgender.

Reference is again made to FIG. 4, which is a graph illustratingbreathing rate patterns of a chronic asthma patient, measured during anexperiment conducted in accordance with an embodiment of the presentinvention. Using techniques described herein, breathing pattern analysismodule 22 compares the pattern of line 102 with the baseline pattern ofline 100, in order to predict that the patient may experience anasthmatic episode. Module 22 compares the pattern of line 104 with thebaseline pattern of line 100 in order to assess a progression of theasthmatic episode.

For some applications of the present invention, the deviation frombaseline is defined as the cumulative deviation of the measured patternfrom the baseline pattern. A threshold indicative of a clinicalcondition is set equal to a certain number of standard errors (e.g., onestandard error). Alternatively or additionally, other measures ofdeviation between measured and baseline patterns are used, such ascorrelation coefficient, mean square error, maximal difference betweenthe patterns, and the area between the patterns. Further alternativelyor additionally, pattern analysis module 16 uses a weighted analysisemphasizing specific regions along the patterns, for example, by givingincreased weight (e.g., double weight) to an initial portion of sleep(e.g., the first two hours of sleep) or to specific hours, for exampleas morning approaches (e.g., the hours of 3:00-6:00 a.m.).

Reference is now made to FIGS. 5 and 6, which are graphs of exemplarybaseline and measured breathing rate and heart rate nighttime patterns,respectively, and which are generally similar to FIGS. 6 and 7 of U.S.Pat. No. 7,314,451 to Halperin, which is incorporated herein byreference. Lines 200 and 202 (FIGS. 5 and 6, respectively) representnormal baseline patterns in the absence of an asthma attack. The barsrepresent one standard error. Lines 204 and 206 (FIGS. 5 and 6,respectively) represent patterns during nights prior to an onset of anasthma attack. Detection of the change in pattern between lines 200 and202 and lines 204 and 206, respectively, enables the early prediction ofthe approaching asthma attack, or other approaching adverse clinicalevents.

For some applications of the present invention, pattern analysis module16 is configured to predict the onset of a clinical manifestation ofheart failure, and/or monitor its severity and progression. Module 16typically determines that an episode is imminent when the module detectsincreased breathing rate accompanied by increased heart rate, and/orwhen the monitored breathing and/or heartbeat patterns have specificcharacteristics that relate to heart failure, such as characteristicsthat are indicative of apnea, Cheyne-Stokes Respiration (CSR), and/orperiodic breathing.

In accordance with the data shown in FIG. 5, for some applications, asubject's respiration is detected on first and second days over similartime durations and at similar time periods (e.g., during the first two,three four, five, or six hours of the subject's sleep). A parameter ofthe subject's respiration based upon the detected respiration rate onthe second day is compared with that of the first day. An alert isgenerated in response to the comparison indicating that an adverseclinical event is approaching, e.g., in response to determining that thedifference between the median, the mean, and/or the maximum respirationrate on the second day and that of the first day exceeds a threshold.

In accordance with the data shown in FIG. 6, for some applications, asubject's heart rate is detected on first and second days over similartime durations and at similar time periods (e.g., during the first two,three, four, five, or six hours of the subject's sleep). A parameter ofthe subject's cardiac cycle based upon the detected heart rate on thesecond day is compared with that of the first day. An alert is generatedin response to the comparison indicating that an adverse clinical eventis approaching, e.g., in response to determining that the differencebetween the median, the mean, and/or the maximum heart rate on thesecond day and that of the first day exceeds a threshold.

In accordance with the data shown in FIGS. 5 and 6, for someapplications, a subject's respiration rate and heart rate are detectedon first and second days over similar time durations and at similar timeperiods (e.g., during the first two, three four, five, or six hours ofthe subject's sleep). A parameter of the subject's respiration basedupon the detected respiration rate on the second day is compared withthat of the first day, and a parameter of the subject's cardiac cyclebased upon the detected heart rate on the second day is compared withthat of the first day. An alert is generated in response to thecomparisons indicating that an adverse clinical event is approaching,e.g., in response to determining that (a) the difference between themedian, the mean, and/or the maximum respiration rate on the second dayand that of the first day exceeds a threshold, and/or (b) the differencebetween the median, the mean, and/or the maximum heart rate on thesecond day and that of the first day exceeds a threshold.

Reference is now made to FIG. 7, which is the same as FIG. 23 of U.S.Pat. No. 7,314,451 to Halperin, which is incorporated herein byreference. FIG. 7 is a graph of baseline and breathing rate nighttimepatterns, respectively, measured in accordance with some applications ofthe present invention. A line 400 represents a normal baseline patternin the absence of Cheyne-Stokes Respiration, and a line 402 represents apattern during a night during CSR. The bars represent one standarderror. In accordance with the data shown in FIG. 7, for someapplications, a subject's respiration is detected on first and seconddays over similar time durations and at similar time periods (e.g.,during the first two, three four, five, or six hours of the subject'ssleep). A parameter of the subject's respiration based upon the detectedrespiration rate on the second day is compared with that of the firstday. An alert is generated in response to the comparison indicating thatan adverse clinical event is approaching, e.g., in response todetermining that the difference between the median, the mean, and/or themaximum respiration rate on the second day and that of the first dayexceeds a threshold.

For some applications, techniques described herein are used inconjunction with techniques as are generally described in pending US2007/0118054 to Pinhas which is incorporated herein by reference. Forexample, as is described with reference to FIG. 18 of pending US2007/0118054 to Pinhas (which is pending), for some applications, system10 is adapted to monitor multiple clinical parameters such asrespiration rate, heart rate, cough occurrence, body movement, deepinspirations, expiration/inspiration ratio, of subject 12. Patternanalysis module 16 is adapted to analyze the respective patterns inorder to identify a change in the baseline pattern of the clinicalparameters. In some cases, this change, a new baseline that issignificantly different from the previous baseline indicates, forexample, a change in medication and provides the caregiver or healthcareprofessional with feedback on the efficacy of treatment.

For some applications, system 10 calculates the average respiration rateand heart rate for predefined time segments. Such time segments can beminutes, hours, or days. By analyzing the history of the patient thesystem can calculate the correlation of respiration rate and heart ratepatterns. When an onset of an asthma attack approaches the correlationof heart rate and respiration rate pattern shows a clear change. Foreach night the respiration rate and heart rate in sleep during the hoursof 11:00 pm to 6:00 am (or over a different time period) is averaged.For each date, a respiration vector of length N with the averagerespiration rate of the last N nights and a heart rate vector of lengthN with the average heart rate for the last N nights is defined. N istypically between 3 and 30, for example 10. The correlation coefficientof the heart rate vector and the respiration vector is calculated foreach date by system 10. A moving window of several days is used tocalculate correlation coefficient changes between the respiration andheart rate vectors. A steady correlation coefficient pattern over atleast several days is required to identify a significant change ofcorrelation coefficient from one time interval to another. A significantchange is defined as a change in the correlation coefficient level of amagnitude larger than the typical correlation coefficient variation inthe previous time interval, e.g., a change larger than 3 standarddeviations of the correlation coefficient signal in the previous timeinterval. System 10 identifies such a significant change as anindication of an approaching clinical event.

As described in US 2007/0118054 to Pinhas, for some applications, duringsleep, sleep stage is identified using techniques described therein. Foreach identified sleep stage, the average respiration rate, heart rateand other clinical parameters are calculated. This data is compared tobaseline defined for that subject for each identified sleep stage, inorder to identify the onset or progress of a clinical episode.

For some applications, for each night, for each hour (or for longerdurations of time, such as more than two hours, as describedhereinabove) of sleep, counted from the onset of sleep, the averagerespiration rate, heart rate and other clinical parameters arecalculated. This data is compared to baseline in order to identify theonset or progress of a clinical episode.

For some applications, for each night, for each hour (or for longerdurations of time, such as more than two hours, as describedhereinabove), the average respiration rate, heart rate and otherclinical parameters are calculated. This data is compared to baseline inorder to identify the onset or progress of a clinical episode. Forexample, the average respiration rate in sleep during 2:00 AM-3:00 AM iscalculated and compared to baseline for that subject in order toidentify the onset or progress of a clinical episode.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

The invention claimed is:
 1. Apparatus, comprising: a mechanical sensorconfigured to detect a physiological signal of a subject withoutcontacting or viewing the subject or clothes that the subject iswearing; a control unit configured to: receive the physiological signalfrom the sensor over a time duration of at least two hours at a givenperiod of at least one first baseline day, determine a physiologicalparameter of the subject based upon the received physiological signal ofthe first baseline day; receive the physiological signal from the sensorover a time duration of at least two hours at a given period of a secondday, the period over which the subject's physiological signal isdetected on the second day overlapping with the period over which thesubject's physiological signal is detected on the first baseline day;determine a physiological parameter of the subject based upon thereceived physiological signal of the second day; compare thephysiological parameter based upon the received physiological signal ofthe second day to the baseline physiological parameter of the subject;and generate an alert in response to the comparison; and an output unitconfigured to output the alert.
 2. The apparatus according to claim 1,wherein the physiological sensor is configured to detect thephysiological signal of the subject by detecting a respiration rate ofthe subject.
 3. The apparatus according to claim 1, wherein thephysiological sensor is configured to detect the physiological signal ofthe subject by detecting a heart rate of the subject.
 4. The apparatusaccording to claim 1, wherein the physiological sensor is configured todetect the physiological signal of the subject by detecting a parameterof motion of the subject.
 5. Apparatus, comprising: a mechanical sensorconfigured to detect a respiration signal indicative of a respirationrate of a subject without contacting or viewing the subject or clothesthat the subject is wearing; and a control unit configured to: receivethe detected respiration signal from the sensor over a time duration ofat least two hours at a given period of at least one firstrespiration-rate baseline day; determine a baseline parameter of thesubject's respiration based upon the received respiration signal of thefirst respiration-rate baseline day; receive the detected respirationsignal from the sensor over a time duration of at least two hours at agiven period of a second day, the period over which the subject'srespiration is detected on the second day overlapping with the periodover which the subject's respiration is detected on the firstrespiration-rate baseline day; determine a parameter of the subject'srespiration based upon the received respiration signal of the secondday; compare the parameter of the subject's respiration based upon thereceived respiration signal of the second day to the baseline parameterof the subject's respiration; and generate an alert in response to thecomparison; and an output unit configured to output the alert.
 6. Theapparatus according to claim 5, wherein the control unit is configuredto determine the baseline parameter of respiration by determining abaseline respiration pattern based upon the received respiration signalof the first respiration-rate baseline day, and wherein the control unitis configured to determine the parameter of the subject's respirationbased upon the received respiration signal of the second day bydetermining a respiration pattern based upon the received respirationsignal of the second day.
 7. The apparatus according to claim 5,wherein: the control unit is configured to determine the baselineparameter of respiration by determining a parameter selected from thegroup consisting of: a mean respiration rate, a maximum respirationrate, and a median respiration rate, based upon the received respirationsignal of the first respiration-rate baseline day, and the control unitis configured to determine the parameter of the subject's respirationbased upon the received respiration signal of the second day bydetermining a parameter selected from the group consisting of: a meanrespiration rate, a maximum respiration rate, and a median respirationrate, based upon the received respiration signal of the second day. 8.The apparatus according to claim 5, wherein the control unit isconfigured to: receive a heart-rate signal from the sensor indicative ofa heart rate of the subject over a time duration of at least two hoursat a given period of at least one first heart-rate baseline day;determine a baseline parameter of the subject's cardiac cycle based uponthe received heart-rate signal of the first heart-rate baseline day;receive a heart-rate signal from the sensor indicative of a heart rateof the subject over a time duration of at least two hours at the givenperiod of the second day, the period over which the subject's heart rateis detected on the second day overlapping with the period over which thesubject's heart rate is detected on the first heart-rate baseline day;determine a parameter of the subject's cardiac cycle based upon thereceived heart-rate signal of the second day; and compare the parameterof the subject's cardiac cycle based upon the received heart-rate signalof the second day to the baseline parameter of the cardiac cycle, andgenerate the alert by generating the alert in response to (a) thecomparison of the parameter of the subject's respiration based upon thereceived respiration signal of the second day to the baseline parameterof the subject's respiration, and (b) the comparison of the parameter ofthe subject's cardiac cycle based upon the received heart-rate signal ofthe second day to the baseline parameter of the subject's cardiac cycle.9. The apparatus according to claim 5, wherein the control unit isconfigured to: receive a motion signal from the sensor indicative ofmotion of the subject over a time duration of at least two hours at agiven period of at least one first motion-parameter baseline day;determine a baseline parameter of the subject's motion based upon thereceived motion signal of the first motion-parameter baseline day;receive a motion signal from the sensor indicative of motion of thesubject over a time duration of at least two hours at the given periodof the second day, the period over which the subject's motion isdetected on the second day overlapping with the period over which thesubject's motion is detected on the first motion-parameter baseline day;determine a parameter of the subject's motion based upon the receivedmotion signal of the second day; and compare the parameter of thesubject's motion based upon the received motion signal of the second dayto the baseline parameter of motion, and generate the alert bygenerating the alert in response to (a) the comparison of the parameterof the subject's respiration based upon the received respiration signalof the second day to the baseline parameter of the subject'srespiration, and (b) the comparison of the parameter of the subject'smotion based upon the received motion signal of the second day to thebaseline parameter of the subject's motion.
 10. The apparatus accordingto claim 5, wherein the control unit is configured to compare theparameter of the subject's respiration based upon the receivedrespiration signal of the second day to the baseline parameter of thesubject's respiration by determining whether the parameter of thesubject's respiration based upon the received respiration signal of thesecond day differs from the baseline parameter of the subject'srespiration by more than a threshold amount.
 11. The apparatus accordingto claim 10, wherein the control unit is configured to: receive aheart-rate signal from the sensor indicative of a heart rate of thesubject; and set the threshold in response to the detected heart-ratesignal.
 12. The apparatus according to claim 10, wherein the controlunit is configured to: receive a motion signal from the sensorindicative of a motion of the subject; and set the threshold in responseto the detected motion signal.
 13. Apparatus, comprising: a mechanicalsensor configured to detect a heart-rate signal indicative of a heartrate of a subject without contacting or viewing the subject or clothesthat the subject is wearing; and a control unit configured to: receivethe detected heart-rate signal from the sensor over a time duration ofat least two hours at a given period of at least one first heart-ratebaseline day; determine a baseline parameter of the subject's cardiaccycle based upon the received heart-rate signal of the first heart-ratebaseline day; receive the detected heart-rate signal from the sensorover a time duration of at least two hours at a given period of a secondday, the period over which the subject's heart rate is detected on thesecond day overlapping with the period over which the subject's heartrate is detected on the first heart-rate baseline day; determine aparameter of the subject's cardiac cycle based upon the receivedheart-rate signal of the second day; compare the parameter of thesubject's cardiac cycle based upon the received heart-rate signal of thesecond day to the baseline parameter of the subject's cardiac cycle; andgenerate an alert in response to the comparison; and an output unitconfigured to output the alert.
 14. The apparatus according to claim 13,wherein the control unit is configured to: receive a motion signal fromthe sensor indicative of motion of the subject over a time duration ofat least two hours at a given period of at least one firstmotion-parameter baseline day; determine a baseline parameter of thesubject's motion based upon the received motion signal of the firstmotion-parameter baseline day; receive a motion signal from the sensorindicative of motion of the subject over a time duration of at least twohours at the given period of the second day, the period over which thesubject's motion is detected on the second day overlapping with theperiod over which the subject's motion is detected on the firstmotion-parameter baseline day; determine a parameter of the subject'smotion based upon the received motion signal of the second day; andcompare the parameter of the subject's motion based upon the receivedmotion signal of the second day to the baseline parameter of motion, andgenerate the alert by generating the alert in response to (a) thecomparison of the parameter of the subject's cardiac cycle based uponthe received heart-rate signal of the second day to the baselineparameter of the subject's cardiac cycle, and (b) the comparison of theparameter of the subject's motion based upon the received motion signalof the second day to the baseline parameter of the subject's motion. 15.The apparatus according to claim 13, wherein the control unit isconfigured to compare the parameter of the subject's cardiac cycle basedupon the received heart-rate signal of the second day to the baselineparameter of the subject's cardiac cycle by determining whether theparameter of the subject's cardiac cycle based upon the receivedheart-rate signal of the second day differs from the baseline parameterof the subject's cardiac cycle by more than a threshold amount.
 16. Theapparatus according to claim 15, wherein the control unit is configuredto: receive a respiration signal from the sensor indicative of arespiration rate of the subject; and set the threshold in response tothe detected respiration signal.
 17. The apparatus according to claim15, wherein the control unit is configured to: receive a motion signalfrom the sensor indicative of a motion of the subject; and set thethreshold in response to the detected motion signal.